Cognitive impairment has a serious detrimental impact on the quality of life for prostate cancer survivors treated by androgen deprivation therapy (ADT). Neuroimaging studies have shown structural and functional deficits in the medial prefrontal cortex (mPFC) and hippocampus (Hipp), which mediate higher order cognitive processes, including cognitive flexibility and spatial cognition, that are impaired after ADT. In this project, we will investigate mechanisms that underly the cognitive impairments we have now shown to be induced by androgen deprivation in rats. Also, as there is currently no satisfactory treatment for cognitive impairment after ADT, we will test the efficacy of vortioxetine, a novel multi-modal antidepressant drug that has been shown to have specific and unique positive effects on cognitive impairment in depression, in potentially reversing cognitive impairment after ADT. Similar to SSRIs, vortioxetine blocks the serotonin transporter, but it also has direct actions on several pre- and post-synaptic serotonin receptors that give it additional efficacy against symptoms of depression that are often resistant to treatment, including cognitive impairment. To assess mPFC-mediated cognitive function in rats, we will use the Attentional Set-shifting Test (AST). And to assess spatial cognition mediated in the hippocampus (Hipp), we will use the Novel Object Location (NOL) test. We have already shown that ADT induces an impairment in cognitive set-shifting. Thus in aim 1A, we will complete the pilot study in which we have preliminary data showing a spatial cognition deficit in the NOL test as well. In addition, there are many factors to consider in the full context of treating prostate cancer. Thus, in the rest of aim 1, together with ADT and vortioxetine, we will investigate the interacting influences of factors including age-related cognitive decline; an alternate method of inducing ADT with the GnRH antagonist degarelix; and chemotherapy with docetaxel. Indeed, because of recent changes to standard of care, we will also include docetaxel in all subsequent aims. In aim 2, we will then study neural processes related to functional plasticity that may underly the cognitive effects of ADT and vortioxetine, measuring changes in electrical response evoked in mPFC by stimulating afferents from the mediodorsal thalamus (MDT) and ventral Hipp, an indication of synaptic efficacy and functional integrity of cortical circuits. In aim 3, we will study processes related to structural plasticity, measuring changes in dendritic complexity and synaptic spine density and morphology on pyramidal cells that drive the behavioral output of the mPFC and Hipp. Effects of androgens are mediated by gene transcription and protein expression. Thus, in aim 4, we will assess changes in gene expression in the mPFC and Hipp by microarray analysis, then use a ?candidate factor? approach to investigate changes in mRNA and protein expression and phosphorylation of specific plasticity-related signaling molecules. The results of this project may identify new targets for treating cognitive impairment after ADT, and they may reveal new mechanisms underlying the efficacy of vortioxetine.